The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts
The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts
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DOI：
10.1093/emboj/18.6.1571
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发表时间：
1999-03-15
期刊：
影响因子：
11.4
通讯作者：
Sherr, CJ
中科院分区：
文献类型：
--
作者：
Cheng, MG;Olivier, P;Sherr, CJ
细胞周期蛋白D-CDK4在有丝分裂原刺激的成纤维细胞中的正常上调依赖于p21(Cip1)和p27(Kip1)，这一普遍流行的观点受到了挑战。缺乏编码p21和p27基因的原代小鼠胚胎成纤维细胞不能组装可检测到的Cyclin D-CDK复合体，表达Cyclin D蛋白的水平大大降低，并且不能有效地将Cyclin D蛋白定向到细胞核。CKI功能的恢复可以逆转所有这三种缺陷，从而将细胞周期蛋白D的活性恢复到正常的生理水平。在没有这两个CKI的情况下，细胞周期蛋白D依赖的激酶活性的严重降低是可以很好地耐受的，并且对细胞周期没有明显的影响。
The widely prevailing view that the cyclin-dependent kinase inhibitors (CKIs) are solely negative regulators of cyclin-dependent kinases (CDKs) is challenged here by observations that normal up-regulation of cyclin D-CDK4 in mitogen-stimulated fibroblasts depends redundantly upon p21(Cip1) and p27(Kip1). Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to assemble detectable amounts of cyclin D-CDK complexes, express cyclin D proteins at much reduced levels, and are unable to efficiently direct cyclin D proteins to the cell nucleus. Restoration of CKI function reverses all three defects and thereby restores cyclin D activity to normal physiological levels. In the absence of both CKIs, the severe reduction in cyclin D-dependent kinase activity was well tolerated and had no overt effects on the cell cycle.